Tissue-engineered human asthmatic bronchial equivalents

Paquette, J. C.; Moulin, Véronique; Tremblay, Pierre; Bernier, Vincent; Boutet, M; Laviolette, Michel; Fa, Auger; Boulet, L.-P.; Goulet, Francine

doi:10.22203/ecm.v007a01

Cited by 41 publications

(27 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several research groups, including our own, have recently demonstrated the advantages of three-dimensional airway co-culture models that provide an ECM and organization of a cellular community over traditional (two-dimensional, single-cell) culture models for recapitulating physiologic and pathophysiologic behavior (38)(39)(40)(41). Our model here additionally mimics the mechanical function of the smooth muscle cells by incorporating lateral and dynamic compression to the three-dimensional culture system over a long-term period.…”

mentioning

confidence: 99%

Extracellular Matrix Remodeling by Dynamic Strain in a Three-Dimensional Tissue-Engineered Human Airway Wall Model

Choe

Sporn

Swartz

2006

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Airway wall remodeling is a hallmark of asthma, characterized by subepithelial thickening and extracellular matrix (ECM) remodeling. Mechanical stress due to hyperresponsive smooth muscle cells may contribute to this remodeling, but its relevance in a threedimensional environment (where the ECM plays an important role in modulating stresses felt by cells) is unclear. To characterize the effects of dynamic compression in ECM remodeling in a physiologically relevant three-dimensional environment, a tissue-engineered human airway wall model with differentiated bronchial epithelial cells atop a collagen gel containing lung fibroblasts was used. Lateral compressive strain of 10 or 30% at 1 or 60 cycles per hour was applied using a novel straining device. ECM remodeling was assessed by immunohistochemistry and zymography. Dynamic strain, particularly at the lower magnitude, induced airway wall remodeling, as indicated by increased deposition of types III and IV collagen and increased secretion of matrix metalloproteinase-2 and -9. These changes paralleled increased myofibroblast differentiation and were fibroblast-dependent. Furthermore, the spatial pattern of type III collagen deposition correlated with that of myofibroblasts; both were concentrated near the epithelium and decreased diffusely away from the surface, indicating some epithelial control of the remodeling response. Thus, in a physiologically relevant three-dimensional model of the bronchial wall, dynamic compressive strain induced tissue remodeling that mimics many features of remodeling seen in asthma, in the absence of inflammation and dependent on epithelial-fibroblast signaling.Keywords: asthma; collagen; fibrosis; in vitro; myofibroblast Remodeling of the airway wall in asthma is characterized by thickening of the subepithelial lamina reticularis, increase in smooth muscle mass, fibroblast hyperplasia, mucus hypersecretion, edema, and angiogenesis (1-6). The subepithelial fibrosis that is often part of this remodeling is further characterized by the differentiation of fibroblasts to myofibroblasts, which are more contractile than fibroblasts and are likely to contribute to the alignment and stiffening of the airway matrix by secretion of types I, III, and V collagen (7-14). In addition, matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]), particularly MMP-2 and -9 and TIMP-1, are also increased in the airways in asthma, as they are key players in extracellular matrix (ECM) remodeling (15, 16). Evidence from clinical studies supports the concept that airway remodeling contributes to irreversible airflow obstruction and loss of pulmonary function over time in patients with chronic asthma (17, 18).The complex interplay of factors contributing to airway wall remodeling, which includes inflammatory and mechanical factors, is not well understood. Immune cells recruited to the inflamed airways release cytokines such as RANTES (CCL5), IL-13, TGF-␤ 1 , and cysteinyl leukotrienes C4, D4, and E4 (19-21) that c...

show abstract

mentioning

confidence: 99%

Extracellular Matrix Remodeling by Dynamic Strain in a Three-Dimensional Tissue-Engineered Human Airway Wall Model

Choe

Sporn

Swartz

2006

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…The utility of previously developed in vitro models for studying transepithelial transport-related phenomena is limited by the level of bronchial epithelial cell differentiation and ciliary function attainable (10 -12, 50, 51, 55). Culture conditions that were previously developed to promote epithelial differentiation towards a pseudostratified state include coculture with fibroblasts within a 3D matrix (1,11,50,51,63,64,75), the addition of specific factors to a serum-free media (15,27,55), and culture in ALI after epithelial cells have reached confluence (3,15,18,49,65). We further optimized the medium composition for ciliogenesis and cultured for 21 days at ALI.…”

Section: Discussionmentioning

confidence: 99%

Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model

Tomei¹,

Choe²

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Tomei AA, Choe MM, Swartz MA. Effects of dynamic compression on lentiviral transduction in an in vitro airway wall model. Am J Physiol Lung Cell Mol Physiol 294: L79-L86, 2008. First published November 16, 2007 doi:10.1152/ajplung.00062.2007.-Asthmatic patients are more susceptible to viral infection, and we asked whether dynamic strain on the airway wall (such as that associated with bronchoconstriction) would influence the rate of viral infection of the epithelial and subepithelial cells. To address this, we characterized the barrier function of a three-dimensional culture model of the bronchial airway wall mucosa, modified the culture conditions for optimization of ciliogenesis, and compared epithelial and subepithelial green fluorescent protein (GFP) transduction by a pWpts-GFP lentivirus, pseudotyped with VSV-G, under static vs. dynamic conditions. The model consisted of human lung fibroblasts, bronchial epithelial cells, and a type I collagen matrix, and after 21 days of culture at air liquid interface, it exhibited a pseudostratified epithelium comprised of basal cells, mucus-secreting cells, and ciliated columnar cells with beating cilia. Microparticle tracking revealed partial coordination of mucociliary transport among groups of cells. Slow dynamic compression of the airway wall model (15% strain at 0.1 Hz over 3 days) substantially enhanced GFP transduction of epithelial cells and underlying fibroblasts. Fibroblast-only controls showed a similar degree of transduction enhancement when undergoing dynamic strain, suggesting enhanced transport through the matrix. Tight junction loss in the epithelium after mechanical stress was observed by immunostaining. We conclude that dynamic compressive strain such as that associated with bronchoconstriction may promote transepithelial transport and enhance viral transgene delivery to epithelial and subepithelial cells. This finding has significance for asthma pathophysiology as well as for designing delivery strategies of viral gene therapies to the airways. mechanical stress; three-dimensional model; asthma; bronchoconstriction; ciliogenesis; human ASTHMA AND AIRWAY SUSCEPTIBILITY to viral infections have long been correlated clinically (2,9,16,26,36,61,62). Asthma is associated with recruitment of inflammatory cells, remodeling and thickening of the reticular basement membrane, subepithelial fibrosis, and airway smooth muscle hyperresponsiveness and hyperreactivity (reviewed in Refs. 7,17,19,21,23,25,48,70). The epithelial barrier function of asthmatic airways is often damaged (35), possibly increasing susceptibility to viral infection. Moreover, it has been shown that epithelial cells from asthmatic patients express a higher number of viral receptors on their surface (4, 62), which when activated exacerbate epithelial secretion of cytokines like granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6, IL-8, IL-11, and RANTES that help maintain a persistent inflammatory state (46).Nevertheless, inflammatory mediators are only part of the story, as ...

show abstract

“…Several biocompatible and biodegradable scaffolding materials have been explored for the engineering of 3-D lung tissues. Initial and obvious choices are natural ECM proteins such as collagen (29,71,145,146,191). However, due to its low mechanical properties in loose hydrogel configurations, collagen by itself is not load-bearing unless it is cross-linked or mechanically compressed, which may separately be relevant to the issue of reduced recellularization potential, and reduced flexibility of the scaffold for eventual use.…”

Section: L629mentioning

confidence: 99%